[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

EP1165551B1 - Taxanes substitues par carbamoyloxy au niveau de c10 en tant qu'agents antitumoraux - Google Patents

Taxanes substitues par carbamoyloxy au niveau de c10 en tant qu'agents antitumoraux Download PDF

Info

Publication number
EP1165551B1
EP1165551B1 EP01905434A EP01905434A EP1165551B1 EP 1165551 B1 EP1165551 B1 EP 1165551B1 EP 01905434 A EP01905434 A EP 01905434A EP 01905434 A EP01905434 A EP 01905434A EP 1165551 B1 EP1165551 B1 EP 1165551B1
Authority
EP
European Patent Office
Prior art keywords
thienyl
ncoo
taxane
pyridyl
alkenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP01905434A
Other languages
German (de)
English (en)
Other versions
EP1165551A1 (fr
Inventor
Robert A. Florida State University HOLTON
Weishuo Florida State University FANG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Florida State University Research Foundation Inc
Original Assignee
Florida State University Research Foundation Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Florida State University Research Foundation Inc filed Critical Florida State University Research Foundation Inc
Publication of EP1165551A1 publication Critical patent/EP1165551A1/fr
Application granted granted Critical
Publication of EP1165551B1 publication Critical patent/EP1165551B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is directed to novel taxanes which have exceptional utility as antitumor agents.
  • Taxol itself is employed as a cancer chemotherapeutic agent and possesses a broad range of tumor-inhibiting activity. Taxol has a 2'R, 3'S configuration and the following structural formula: wherein Ac is acetyl.
  • taxol and docetaxel are useful chemotherapeutic agents, there are limitations on their effectiveness, including limited efficacy against certain types of cancers and toxicity to subjects when administered at various doses. Accordingly, a need remains for additional chemotherapeutic agents with improved efficacy and less toxicity.
  • taxanes which compare favorably to taxol and docetaxel with respect to efficacy as anti-tumor agents and with respect to toxicity.
  • these taxanes possess a carbamoyloxy substituent at C-10, a hydroxy substituent at C-7 and a range of C-3' substituents, as defined in the claims.
  • the present invention is directed to the taxane composition, per se, to pharmaceutical compositions comprising the taxane and a pharmaceutically acceptable carrier, and to methods of administration.
  • taxanes of the present invention correspond to structure (2): wherein
  • X 3 is thienyl or pyridyl; and X 5 is preferably alkoxycarbonyl, more preferably t-butoxycarbonyl or t-amyloxycarbonyl.
  • R 7 and R 10 may each have the beta stereochemical configuration, R 7 and R 10 may each have the alpha stereochemical configuration, R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration or R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
  • Taxanes having the general formula 2 may be obtained by carbamoylation of a suitably protected taxane intermediate having the structural formula: wherein X 3 and X 5 are as previously defined, P 2 is a hydroxy protecting group, and P 7 is either hydrogen or a hydroxy protecting group, by reaction with an isocyanate or a carbamoyl chloride, followed by removal of the hydroxy protecting group(s).
  • the intermediate taxane may be obtained by treatment of a ⁇ -lactam with an alkoxide having the taxane tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a ⁇ -amido ester substituent at C-13 (as described more fully in Holton U.S. Patent 5,466,834 ), followed by removal of either the C(10) protecting group, or both the C(10) and C(7) protecting groups.
  • the ⁇ -lactam has the formula (3): wherein P 2 is a hydroxy protecting group and X 3 and X 5 are as previously defined and the alkoxide has the formula (4): wherein M is a metal or ammonium, and P 7 and P 10 are hydroxy protecting groups.
  • the alkoxide may be prepared from 10-deacetylbaccatin III by protection of the C-7 and C-10 hydroxyl groups (as described more fully in Holton et al., PCT Patent Application WO 99/09021 ) followed by treatment with a metallic amide.
  • Taxane derivatives having acyloxy substituents other than benzoyloxy at C(2) may be prepared, for example, as described in Holton et al., U.S. Patent No. 5,728,725 or Springfield et al., U.S. Patent No. 6,002,023 .
  • Taxanes having acyloxy or hydroxy substituents at C(9) in place of keto may be prepared, for example as described in Holton et al., U.S. Patent No. 6,011,056 or Gunawardana et al., U.S. Patent No. 5,352,806 .
  • Taxanes having a beta hydroxy substituent at C(14) may be prepared from naturally occurring 14-hydroxy-10-deacetylbaccatin III.
  • the ⁇ -lactam may be prepared as described in Holton, U.S. Patent No. 5,430,160 and the resulting enatiomeric mixtures of ⁇ -lactams may be resolved by a stereoselective hydrolysis using a lipase or enzyme as described, for example; in Patel, U.S. Patent No. 5,879,929 Patel U.S. Patent No. 5,567,614 or a liver homogenate as described, for example, in PCT Patent Application No. 00/41204 .
  • the ⁇ -lactam can be prepared as illustrated in the following reaction scheme: wherein Ac is acetyl, NEt 3 is triethylamine, CAN is ceric ammonium nitrate, and p-TsOH is p-toluenesulfonic acid.
  • the beef liver resolution may be carried out, for example, by combining the enatiomeric ⁇ -lactam mixture with a beef liver suspension (prepared, for example, by adding 20 g of frozen beef liver to a blender and then adding a pH 8 buffer to make a total volume of 1 L).
  • Compounds of formula 2 of the instant invention are useful for inhibiting tumor growth in mammals including humans and are preferably administered in the form of a pharmaceutical composition comprising an effective antitumor amount of a compound of the instant invention in combination with at least one pharmaceutically or pharmacologically acceptable carrier.
  • the carrier also known in the art as an excipient, vehicle, auxiliary, adjuvant, or diluent, is any substance which is pharmaceutically inert, confers a suitable consistency or form to the composition, and does not diminish the therapeutic efficacy of the antitumor compounds.
  • the carrier is "pharmaceutically or pharmacologically acceptable" if it does not produce an adverse, allergic or other untoward reaction when administered to a mammal or human, as appropriate.
  • compositions containing the antitumor compounds of the present invention may be formulated in any conventional manner. Proper formulation is dependent upon the route of administration chosen.
  • compositions of the invention can be formulated for any route of administration so long as the target tissue is available via that route.
  • Suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrastemal), topical (nasal, transdermal, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoscopical, transmucosal, sublingual and intestinal administration.
  • parenteral e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrastemal
  • topical nasal, transdermal, intraocular
  • intravesical, intrathecal enteral
  • compositions of the present invention are well known to those of ordinary skill in the art and are selected based upon a number of factors: the particular antitumor compound used, and its concentration, stability and intended bioavailability; the disease, disorder or condition being treated with the composition; the subject, its age, size and general condition; and the route of administration. Suitable carriers are readily determined by one of ordinary skill in the art (see, for example, J. G. Naim, in: Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985), pp. 1492-1517 , the contents of which are incorporated herein by reference).
  • compositions are preferably formulated as tablets, dispersible powders, pills, capsules, gelcaps, caplets, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, elixirs, troches, dragees, lozenges, or any other dosage form which can be administered orally.
  • Techniques and compositions for making oral dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979 ); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981 ); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976 ).
  • compositions of the invention for oral administration comprise an effective antitumor amount of a compound of the invention in a pharmaceutically acceptable carrier.
  • suitable carriers for solid dosage forms include sugars, starches, and other conventional substances including lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, com starch, potato starch, sodium saccharin, magnesium carbonate, tragacanth, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, and stearic acid.
  • such solid dosage forms may be uncoated or may be coated by known techniques; e.g., to delay disintegration and absorption.
  • the antitumor compounds of the present invention are also preferably formulated for parenteral administration, e.g., formulated for injection via intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrastemal routes.
  • the compositions of the invention for parenteral administration comprise an effective antitumor amount of the antitumor compound in a pharmaceutically acceptable carrier.
  • Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions or any other dosage form which can be administered parenterally. Techniques and compositions for making parenteral dosage forms are known in the art.
  • Suitable carriers used in formulating liquid dosage forms for oral or parenteral administration include nonaqueous, pharmaceutically-acceptable polar solvents such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water, saline solutions, dextrose solutions (e.g., DW5), electrolyte solutions, or any other aqueous, pharmaceutically acceptable liquid.
  • nonaqueous, pharmaceutically-acceptable polar solvents such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water, saline solutions, dextrose solutions (e.g., DW5), electrolyte solutions, or any other aqueous, pharmaceutically acceptable liquid.
  • Suitable nonaqueous, pharmaceutically-acceptable polar solvents include, but are not limited to, alcohols (e.g., ⁇ -glycerol formal, ⁇ -glycerol formal, 1, 3-butyleneglycol, aliphatic or aromatic alcohols having 2-30 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fatty alcohols such as polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g., dimethylacetamide (DMA), benzy
  • Preferred solvents include those known to stabilize the antitumor compounds, such as oils rich in triglycerides, for example, safflower oil, soybean oil or mixtures thereof, and alkyleneoxy modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor® RH 40 solution).
  • oils rich in triglycerides for example, safflower oil, soybean oil or mixtures thereof
  • alkyleneoxy modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor® RH 40 solution).
  • triglycerides include Intralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Sweden), Nutralipid ® emulsion (McGaw, Irvine, California), Liposyn® II 20% emulsion (a 20% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Illinois), Liposyn® III 2% emulsion (a 2% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Illinois), natural or synthetic glycerol derivatives containing the docosahexaenoyl group at levels between 25% and 100% by weight based on the total fatty acid content (Dhasco® (from Martek Biosciences Corp., Columbia, MD), DHA
  • compositions of the invention for a variety of purposes well known in the pharmaceutical industry. These components will for the most part impart properties which enhance retention of the antitumor compound at the site of administration, protect the stability of the composition, control the pH, facilitate processing of the antitumor compound into pharmaceutical formulations, and the like. Preferably, each of these components is individually present in less than about 15 weight % of the total composition, more preferably less than about 5 weight %, and most preferably less than about 0.5 weight % of the total composition. Some components, such as fillers or diluents, can constitute up to 90 wt.% of the total composition, as is well known in the formulation art.
  • Such additives include cryoprotective agents for preventing reprecipitation of the taxane, surface active, wetting or emulsifying agents (e.g., lecithin, polysorbate-80, Tween® 80, pluronic 60, polyoxyethylene stearate ), preservatives (e.g., ethyl-p-hydroxybenzoate), microbial preservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben), agents for adjusting pH or buffering agents (e.g., acids, bases, sodium acetate, sorbitan monolaurate), agents for adjusting osmolarity (e.g., glycerin), thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose, tristearin, cety
  • a pharmaceutical composition of the invention comprises at least one nonaqueous, pharmaceutically acceptable solvent and an antitumor compound having a solubility in ethanol of at least about 100, 200, 300, 400, 500, 600, 700 or 800 mg/ml. While not being bound to a particular theory, it is believed that the ethanol solubility of the antitumor compound may be directly related to its efficacy.
  • the antitumor compound can also be capable of being crystallized from a solution. In other words, a crystalline antitumor compound, such as compound 1393, can be dissolved in a solvent to form a solution and then recrystallized upon evaporation of the solvent without the formation of any amorphous antitumor compound.
  • the antitumor compound have an ID50 value (i.e, the drug concentration producing 50% inhibition of colony formation) of at least 4, 5, 6, 7, 8, 9, or 10 times less that of paclitaxel when measured according to the protocol set forth in the working examples.
  • ID50 value i.e, the drug concentration producing 50% inhibition of colony formation
  • Dosage form administration by these routes may be continuous or intermittent, depending, for example, upon the patient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to and assessable by a skilled practitioner.
  • Dosage and regimens for the administration of the pharmaceutical compositions of the invention can be readily determined by those with ordinary skill in treating cancer. It is understood that the dosage of the antitumor compounds will be dependent upon the age, sex, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. For any mode of administration, the actual amount of antitumor compound delivered, as well as the dosing schedule necessary to achieve the advantageous effects described herein, will also depend, in part, on such factors as the bioavailability of the antitumor compound, the disorder being treated, the desired therapeutic dose, and other factors that will be apparent to those of skill in the art.
  • an effective amount of the antitumor compound, whether administered orally or by another route, is any amount which would result in a desired therapeutic response when administered by that route.
  • the compositions for oral administration are prepared in such a way that a single dose in one or more oral preparations contains at least 20 mg of the antitumor compound per m 2 of patient body surface area, or at least 50, 100, 150, 200, 300, 400, or 500 mg of the antitumor compound per m 2 of patient body surface area, wherein the average body surface area for a human is 1.8 m 2 .
  • a single dose of a composition for oral administration contains from about 20 to about 600 mg of the antitumor compound per m 2 of patient body surface area, more preferably from about 25 to about 400 mg/m 2, even more preferably, from about 40 to about 300 mg/m 2 , and even more preferably from about 50 to about 200 mg/m 2 .
  • the compositions for parenteral administration are prepared in such a way that a single dose contains at least 20 mg of the antitumor compound per m 2 of patient body surface area, or at least 40, 50, 100, 150, 200, 300, 400, or 500 mg of the antitumor compound per m 2 of patient body surface area.
  • a single dose in one or more parenteral preparations contains from about 20 to about 500 mg of the antitumor compound per m 2 of patient body surface area, more preferably from about 40 to about 400 mg/m 2, and even more preferably, from about 60 to about 350 g/m 2 .
  • the dosage may vary depending on the dosing schedule which can be adjusted as necessary to achieve the desired therapeutic effect. It should be noted that the ranges of effective doses provided herein are not intended to limit the invention and represent preferred dose ranges. The most preferred dosage will be tailored to the individual subject, as is understood and determinable by one of ordinary skill in the art without undue experimentation.
  • the concentration of the antitumor compound in a liquid pharmaceutical composition is preferably between about 0.01 mg and about 10 mg per ml of the composition, more preferably between about 0.1 mg and about 7 mg per ml, even more preferably between about 0.5 mg and about 5 mg per ml, and most preferably between about 1.5 mg and about 4 mg per ml. Relatively low concentrations are generally preferred because the antitumor compound is most soluble in the solution at low concentrations.
  • the concentration of the antitumor compound in a solid pharmaceutical composition for oral administration is preferably between about 5 weight % and about 50 weight %, based on the total weight of the composition, more preferably between about 8 weight % and about 40 weight %, and most preferably between about 10 weight % and about 30 weight %.
  • solutions for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution.
  • a pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride)
  • An appropriate volume of a carrier which is a solution, such as Cremophor® EL solution, is added to the solution while stirring to form a pharmaceutically acceptable solution for oral administration to a patient.
  • a pharmaceutically acceptable solution for oral administration e.g., ethanol or methylene chloride
  • powders or tablets for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g.,ethanol or methylene chloride) to form a solution.
  • the solvent can optionally be capable of evaporating when the solution is dried under vacuum.
  • An additional carrier can be added to the solution prior to drying, such as Cremophor® EL solution.
  • the resulting solution is dried under vacuum to form a glass.
  • the glass is then mixed with a binder to form a powder.
  • the powder can be mixed with fillers or other conventional tabletting agents and processed to form a tablet for oral administration to a patient.
  • the powder can also be added to any liquid carrier as described above to form a solution, emulsion, suspension or the like for oral administration.
  • Emulsions for parenteral administration can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution.
  • An appropriate volume of a carrier which is an emulsion, such as Liposyn® II or Liposyn® III emulsion, is added to the solution while stirring to form a pharmaceutically acceptable emulsion for parenteral administration to a patient.
  • emulsions can be formulated to contain a minimal amount of, or to be free of, ethanol or Cremophor® solution, which are known in the art to cause adverse physiological effects when administered at certain concentrations in parenteral formulations.
  • Solutions for parenteral administration can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution.
  • a pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride)
  • An appropriate volume of a carrier which is a solution, such as Cremophor® solution is added to the solution while stirring to form a pharmaceutically acceptable solution for parenteral administration to a patient.
  • such solutions can be formulated to contain a minimal amount of, or to be free of, ethanol or Cremophor® solution, which are known in the art to cause adverse physiological effects when administered at certain concentrations in parenteral formulations.
  • the emulsions or solutions described above for oral or parenteral administration can be packaged in IV bags, vials or other conventional containers in concentrated form and diluted with any pharmaceutically acceptable liquid, such as saline, to form an acceptable taxane concentration prior to use as is known in the art.
  • hydrocarbon and “hydrocarbyl” as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.
  • alkyl groups described herein are preferably lower alkyl containing from two to six carbon atoms in the principal chain. They may be straight or branched chain or cyclic and include ethyl, propyl, isopropyl, butyl, hexyl and the like.
  • alkenyl groups described herein are preferably lower alkenyl containing from two to six carbon atoms in the principal chain. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
  • aryl or “ar” as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl.
  • halogen or halo as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
  • heterocyclo or “heterocyclic” as used herein alone or as part of another group denote fully saturated or unsaturated, monocyclic or bicyclic, aromatic or nonaromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring.
  • the heterocyclo group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom.
  • heterocyclo include heteroaromatics such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like.
  • heteroaromatic as used herein alone or as part of another group denote aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring.
  • the heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom.
  • Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like.
  • acyl denotes the moiety formed by removal of the hydroxyl group from the group -COOH of an organic carboxylic acid, e.g., RC(O)-, wherein R is R 1 , R 1 O-, R 1 R 2 N-, or R 1 S-, R 1 is hydrocarbyl, or heterocyclo and R 2 is hydrogen, or hydrocarbyl.
  • acyloxy denotes an acyl group as described above bonded through an oxygen linkage (-O-), e.g., RC(O)O- wherein R is as defined in connection with the term "acyl.”
  • alkoxycarbonyloxy moieties described herein comprise lower hydrocarbon moieties.
  • carbamoyloxy moieties described herein are derivatives of carbamic acid in which one of the amine hydrogens is optionally replaced by a hydrocarbyl moiety.
  • hydroxyl protecting group and "hydroxy protecting group” as used herein denote a group capable of protecting a free hydroxyl group ("protected hydroxyl") which, subsequent to the reaction for which protection is employed, may be removed without disturbing the remainder of the molecule.
  • protected hydroxyl a group capable of protecting a free hydroxyl group
  • a variety of protecting groups for the hydroxyl group and the synthesis thereof may be found in " Protective Groups in Organic Synthesis" by T. W. Greene, John Wiley and Sons, 1981, or Fieser & Fieser .
  • Exemplary hydroxyl protecting groups include methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (.beta.-trimethylsilylethoxy)methyl, tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl, t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl.
  • Ac means acetyl; “Bz” means benzoyl; “Et” means ethyl; “Me” means methyl; “Ph” means phenyl; “iPr” means isopropyl; “tBu” and “t-Bu” means tert-butyl; “R” means lower alkyl unless otherwise defined; “py” means pyridine or pyridyl; “TES” means triethylsilyl; “TMS” means trimethylsilyl; “LAH” means lithium aluminum hydride; “10-DAB” means 10-desacetylbaccatin III”; “amine protecting group” includes, but is not limited to, carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate; “protected hydroxy” means - OP wherein P is a hydroxy protecting group; “tBuOCO” and “Boc” mean tert-but
  • Example 2 The procedures described in Example 1 were repeated, but other suitably protected ⁇ -lactams and acylating agents were substituted for the ⁇ -lactam and acylating agent of Example 1 to prepare the series of compounds having the combination of substituents identified in the following table.
  • the following table also includes characterization data for certain of these compounds, along with characterization data for the compound (2722) prepared in Example 1.
  • R 10 is as previously defined including wherein R 10 is R 10a R 10b NCOO- and one of R 10a and R 10b is hydrogen and the other is C 2 to C 6 alkyl such as ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; C 2 to C 6 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; or phenyl.
  • R 10 is as previously defined including wherein R 10 is R 10a R 10b NCOO- and one of R 10a and R 10b is hydrogen and the other is C 2 to C 6 alkyl such as ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; C 2 to C 6 alkenyl such as ethenyl or straight, branched or cyclic propenyl
  • R 10 may be R 10a R 10b NCOO- wherein one of R 10a and R 10b is hydrogen and the other is ethyl, or straight, branched or cyclic propyl.
  • X 5 X 3 R 10 tBuOCO 2-thienyl R 10a R 10b NCOO- tBuOCO 3-thienyl R 10a R 10b NCOO- tBuOCO 2-pyridyl R 10a R 10b NCOO- tBuOCO 3-pyridyl R 10a R 10b NCOO- tBuOCO 4-pyridyl R 10a R 10b NcOO- C 4 H 7 CO- 2-thienyl R 10a R 10b NCOO- C 4 H 7 CO- 3-thienyl R 10a R 10b NCOO- C 4 H 7 CO- 2-pyridyl R 10a R 10b NCOO- C 4 H 7 CO- 3-pyridyl R 10a R 10b NCOO- C 4 H 7 CO- 4-pyridyl R
  • HCT116 Four hundred cells (HCT116) were plated in 60 mm Petri dishes containing 2.7 mL of medium (modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin). The cells were incubated in a CO 2 incubator at 37 °C for 5 h for attachment to the bottom of Petri dishes. The compounds identified in Example 2 were made up fresh in medium at ten times the final concentration, and then 0.3 mL of this stock solution was added to the 2.7 mL of medium in the dish. The cells were then incubated with drugs for 72 h at 37 °C.
  • medium modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Epoxy Compounds (AREA)

Claims (16)

  1. Taxane ayant la formule suivante :
    Figure imgb0017
    R7 représentant un groupe hydroxy ;
    R10 représentant R10aR10bNCOO-, R10a ou R10b représentant un hydrogène et l'autre représentant un alkyle C2-C6, un alkényle C2-C6 ou un phényle ;
    X3 représentant un groupe thiényle ou pyridyle ;
    X5 représentant -COX10 ou -COOX10 ;
    X10 représentant un alkyle C2-C6 ou un alkényle C2-C6 ;
    Ac représentant un groupe acétyle et
    Bz représentant un groupe benzoyle ;
  2. Taxane de la revendication 1, dans lequel X3 représente un groupe 2-thiénylé, 3-thiényle, 2-pyridyle, 3-pyridyle ou 4-pyridyle.
  3. Taxane de la revendication 2, dans lequel X5 représente -COX10 et X10 représente un alkényle C2-C6 ou X5 représente -COOX10 et X10 représente un groupe t-butyle.
  4. Taxane de la revendication 1, dans lequel X3 représente un groupe thiényle.
  5. Taxane de la revendication 4, dans lequel X5 représente -COX10 et X10 représente un alkényle C2-C6 ou X5 représente -COOX10 et X10 représente un groupe t-butyle.
  6. Taxane de la revendication 2, dans lequel X3 représente un groupe 2-thiényle ou 3-thiényle.
  7. Taxane de la revendication 6, dans lequel X5 représente -COX10 et X10 représente un alkényle C2-C6 ou X5 représente -COOX10 et X10 représente un groupe t-butyle.
  8. Taxane de la revendication 1, dans lequel X3 représente un groupe thiényle, R10 représente R10aR10bNCOO-, R10a ou R10b représentant un hydrogène et l'autre R10a ou R10b représentant un alkyle C2-C6 ou un phényle et X5 représente -COX10, X10 représentant un alkényle C2-C6 ou bien X5 représente -COOX10, X10 représentant un groupe t-butyle.
  9. Taxane de la revendication 1, dans lequel X3 représente un groupe thiényle, R10a ou R10b représente un hydrogène et l'autre R10a ou R10b représente un éthyle ou bien un propyle à chaîne droite, ramifiée ou cyclique et X5 représente -COX10, X10 représentant un alkényle C2-C6 ou bien X5 représente -COOX10, X10 représentant un groupe t-butyle.
  10. Taxane de la revendication 1, dans lequel X3 représente un groupe thiényle, R10 représente R10aR10bNCOO-, R10a ou R10b représentant un hydrogène et l'autre R10a ou R10b représentant un phényle et X5 représente -COX10, X10 représentant un alkényle C2-C6 ou bien X5 représente -COOX10, X10 représentant un groupe t-butyle.
  11. Taxane de la revendication 1, dans lequel X3 représente un groupe 2-pyridyle, 3-pyridyle ou 4-pyridyle, X5 représente -COOX10, X10 représentant un groupe t-butyle, et R10 représente R10aR10bNCOO-, R10a ou R10b représentant un hydrogène et l'autre R10a ou R10b représentant un groupe éthyle.
  12. Taxane de la revendication 1, dans lequel X3 représente un 2-thiényle ou un 3-thiényle, X5 représente -COOX10, X10 représentant un groupe t-butyle, et R10 représente R10aR10bNCOO-, R10a ou R10b représentant un hydrogène et l'autre R10a ou R10b représentant un groupe éthyle.
  13. Composition pharmaceutique contenant le taxane de l'une quelconque des revendications précédentes et au moins un porteur pharmaceutiquement acceptable.
  14. Composition de la revendication 13, formulée pour une administration orale.
  15. Utilisation d'un taxane de l'une des revendications 1 à 12 pour la fabrication d'un médicament.
  16. Utilisation d'un taxane de l'une des revendications 1 à 12 pour la fabrication d'un médicament destiné à une administration orale, permettant d'inhiber la croissance d'une tumeur chez un mammifère, ledit médicament contenant une quantité thérapeutiquement active dudit taxane et au moins un porteur pharmaceutiquement acceptable.
EP01905434A 2000-02-02 2001-02-02 Taxanes substitues par carbamoyloxy au niveau de c10 en tant qu'agents antitumoraux Expired - Lifetime EP1165551B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US17979300P 2000-02-02 2000-02-02
US179793P 2000-02-02
PCT/US2001/003633 WO2001057033A1 (fr) 2000-02-02 2001-02-02 Taxanes substitues par carbamoyloxy au niveau de c10 en tant qu'agents antitumoraux

Publications (2)

Publication Number Publication Date
EP1165551A1 EP1165551A1 (fr) 2002-01-02
EP1165551B1 true EP1165551B1 (fr) 2008-07-16

Family

ID=22658023

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01905434A Expired - Lifetime EP1165551B1 (fr) 2000-02-02 2001-02-02 Taxanes substitues par carbamoyloxy au niveau de c10 en tant qu'agents antitumoraux

Country Status (20)

Country Link
US (3) US6596737B2 (fr)
EP (1) EP1165551B1 (fr)
JP (1) JP2003522173A (fr)
KR (1) KR20020000159A (fr)
CN (1) CN1362959A (fr)
AT (1) ATE401325T1 (fr)
AU (1) AU783422B2 (fr)
BR (1) BR0104352A (fr)
CA (1) CA2368541A1 (fr)
CZ (1) CZ20013520A3 (fr)
DE (1) DE60134814D1 (fr)
HK (1) HK1047936A1 (fr)
HU (1) HUP0200721A3 (fr)
IL (1) IL145640A (fr)
MX (1) MXPA01009921A (fr)
NO (1) NO20014760L (fr)
NZ (1) NZ514407A (fr)
PL (1) PL350331A1 (fr)
WO (1) WO2001057033A1 (fr)
ZA (1) ZA200108053B (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL350331A1 (en) * 2000-02-02 2002-12-02 Univ Florida State Res Found C10 carbamoyloxy substituted taxanes as antitumor agents
MXPA01009900A (es) * 2000-02-02 2003-08-20 Univ Florida State Res Found Formulaciones de taxano que tienen solubilidad mejorada.
CN1712399B (zh) * 2004-06-24 2010-08-11 中国医学科学院药物研究所 紫杉醇和免疫增强剂胞壁酰二肽共轭物的制备及用途
EP3252128B1 (fr) * 2006-04-03 2019-01-02 Pharmatherm Chemicals Inc. Procédé d'extraction thermique pour la préparation d'un extrait de taxane
WO2011147330A1 (fr) 2010-05-27 2011-12-01 中国医学科学院药物研究所 Synthèse chimique et effets antitumoraux et antimétastatiques d'un conjugué fonctionnel double
JP6959096B2 (ja) * 2017-10-13 2021-11-02 エイブリック株式会社 充放電制御回路及びこれを備えたバッテリ装置

Family Cites Families (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5175315A (en) 1989-05-31 1992-12-29 Florida State University Method for preparation of taxol using β-lactam
FR2679230B1 (fr) * 1991-07-16 1993-11-19 Rhone Poulenc Rorer Sa Nouveaux derives d'analogues du taxol, leur preparation et les compositions qui les contiennent.
US5350866A (en) 1991-09-23 1994-09-27 Bristol-Myers Squibb Company 10-desacetoxytaxol derivatives
US5227400A (en) 1991-09-23 1993-07-13 Florida State University Furyl and thienyl substituted taxanes and pharmaceutical compositions containing them
US5283253A (en) 1991-09-23 1994-02-01 Florida State University Furyl or thienyl carbonyl substituted taxanes and pharmaceutical compositions containing them
US5721268A (en) 1991-09-23 1998-02-24 Florida State University C7 taxane derivatives and pharmaceutical compositions containing them
US5430160A (en) 1991-09-23 1995-07-04 Florida State University Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides
US5714513A (en) 1991-09-23 1998-02-03 Florida State University C10 taxane derivatives and pharmaceutical compositions
US5243045A (en) 1991-09-23 1993-09-07 Florida State University Certain alkoxy substituted taxanes and pharmaceutical compositions containing them
DK0552041T3 (da) 1992-01-15 2000-10-09 Squibb & Sons Inc Enzymatiske fremgangsmåder til spaltning af enantiomerblandinger af forbindelser, der er nyttige som mellemprodukter ved fr
US5272171A (en) 1992-02-13 1993-12-21 Bristol-Myers Squibb Company Phosphonooxy and carbonate derivatives of taxol
FR2691460B1 (fr) 1992-05-21 1994-07-22 Rhone Poulenc Rorer Sa Nouveaux derives du taxane, leur preparation et les compositions qui les contiennent.
CA2109861C (fr) 1992-12-04 1999-03-16 Shu-Hui Chen Paclitaxels modifies en 6,7
ATE264316T1 (de) 1993-06-11 2004-04-15 Upjohn Co Delta 6,7-taxol derivate antineoplastische verwendung und diese enthaltende pharmazeutische zusammenstellungen
IL109926A (en) 1993-06-15 2000-02-29 Bristol Myers Squibb Co Methods for the preparation of taxanes and microorganisms and enzymes utilized therein
TW397866B (en) 1993-07-14 2000-07-11 Bristol Myers Squibb Co Enzymatic processes for the resolution of enantiomeric mixtures of compounds useful as intermediates in the preparation of taxanes
EP0788493A1 (fr) * 1994-10-28 1997-08-13 The Research Foundation Of State University Of New York Derives taxoides, leur preparation et leur utilisation en tant qu'agents antitumoraux
US6100411A (en) * 1994-10-28 2000-08-08 The Research Foundation Of State University Of New York Taxoid anti-tumor agents and pharmaceutical compositions thereof
FR2732342B1 (fr) * 1995-04-03 1997-04-30 Rhone Poulenc Rorer Sa Nouveaux taxoides, leur preparation et les compositions pharmaceutiques qui les contiennent
FR2732968B1 (fr) 1995-04-14 1997-05-16 Rhone Poulenc Rorer Sa Nouveaux taxoides, leur preparation et les compositions pharmaceutiques qui les contiennent
US5780653A (en) 1995-06-07 1998-07-14 Vivorx Pharmaceuticals, Inc. Nitrophenyl, 10-deacetylated substituted taxol derivatives as dual functional cytotoxic/radiosensitizers
CA2231837A1 (fr) 1995-09-13 1997-03-20 Florida State University Taxanes a effet radiosensibilisant et leurs preparations pharmaceutiques
US6545168B1 (en) 1996-05-06 2003-04-08 Florida State University 1-deoxy baccatin III, 1-deoxy taxol and 1-deoxy taxol analogs and method for the preparation thereof
BR9710366A (pt) * 1996-07-15 1999-08-17 Yakult Honsha Kk Derivados de taxane e drogas que os contêm
US5811452A (en) 1997-01-08 1998-09-22 The Research Foundation Of State University Of New York Taxoid reversal agents for drug-resistance in cancer chemotherapy and pharmaceutical compositions thereof
US5912264A (en) 1997-03-03 1999-06-15 Bristol-Myers Squibb Company 6-halo-or nitrate-substituted paclitaxels
US7288665B1 (en) 1997-08-18 2007-10-30 Florida State University Process for selective derivatization of taxanes
JPH1192468A (ja) 1997-09-17 1999-04-06 Yakult Honsha Co Ltd 新規なタキサン誘導体
KR100551945B1 (ko) * 1997-12-19 2006-02-20 가부시키가이샤 야쿠루트 혼샤 택산 유도체
JP2003026673A (ja) * 1999-03-05 2003-01-29 Asahi Kasei Corp 骨形成促進剤
PL350331A1 (en) * 2000-02-02 2002-12-02 Univ Florida State Res Found C10 carbamoyloxy substituted taxanes as antitumor agents
MXPA01009900A (es) * 2000-02-02 2003-08-20 Univ Florida State Res Found Formulaciones de taxano que tienen solubilidad mejorada.
BR0104358A (pt) 2000-02-02 2002-01-02 Univ Florida State Res Found Formulações de taxana tendo solubilidade aperfeiçoada
GB2370649B (en) * 2000-11-09 2003-06-25 Toppan Printing Co Ltd Measurement of rate of transmission of a vapour through a sample

Also Published As

Publication number Publication date
US7230013B2 (en) 2007-06-12
US6906088B2 (en) 2005-06-14
IL145640A0 (en) 2002-06-30
JP2003522173A (ja) 2003-07-22
CA2368541A1 (fr) 2001-08-09
HK1047936A1 (zh) 2003-03-14
HUP0200721A2 (hu) 2002-07-29
WO2001057033A1 (fr) 2001-08-09
DE60134814D1 (de) 2008-08-28
CN1362959A (zh) 2002-08-07
AU783422B2 (en) 2005-10-27
CZ20013520A3 (cs) 2002-03-13
NO20014760L (no) 2001-11-30
US20050182098A1 (en) 2005-08-18
HUP0200721A3 (en) 2005-02-28
NZ514407A (en) 2004-12-24
MXPA01009921A (es) 2003-08-01
PL350331A1 (en) 2002-12-02
US6596737B2 (en) 2003-07-22
ZA200108053B (en) 2003-12-01
KR20020000159A (ko) 2002-01-04
US20040034230A1 (en) 2004-02-19
US20020077341A1 (en) 2002-06-20
EP1165551A1 (fr) 2002-01-02
AU3331301A (en) 2001-08-14
NO20014760D0 (no) 2001-10-01
ATE401325T1 (de) 2008-08-15
IL145640A (en) 2007-02-11
BR0104352A (pt) 2002-01-02

Similar Documents

Publication Publication Date Title
EP1183253B1 (fr) Taxanes substitues par ester en c7 utilises comme agents anticancereux
EP1165068B1 (fr) Acetate taxanes heterosubstituees en c10 comme agents anti-tumoraux
EP1200424B1 (fr) Taxanes d'acetate c7-heterosubstituees utilisees en tant qu'agents antitumoraux
EP1165551B1 (fr) Taxanes substitues par carbamoyloxy au niveau de c10 en tant qu'agents antitumoraux
EP1165553B1 (fr) Taxanes substitues par un ester en c10 comme agents antitumoraux
US6359154B2 (en) C7 carbamoyloxy substituted taxanes
EP1165552A1 (fr) Taxanes a carbonate substitue en c7 utilises comme agents antitumoraux

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

17P Request for examination filed

Effective date: 20020131

17Q First examination report despatched

Effective date: 20030314

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REF Corresponds to:

Ref document number: 60134814

Country of ref document: DE

Date of ref document: 20080828

Kind code of ref document: P

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

NLV1 Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081216

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081027

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20090305

Year of fee payment: 9

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20090417

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20090227

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20090331

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090228

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090228

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090228

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20091030

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081016

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090302

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20100202

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081017

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100202

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100901

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100202

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090202

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716